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Yakult’s research activities: Inheritance and practice of Shirota-ism

AUTHOR Osamu Chonan,

ADDRESS Research Management Center, Yakult Central Institute, 5-11 Izumi, Kunitachi-shi, Tokyo, 186-8650, Japan

e contribute to the microorganisms in particular,” health and happiness we will continue to work for the Wof people around benefit of our stakeholders, and the world through our pursuit of first and foremost, our customers. excellence in life science in general and our research and experience THE BEGINNING OF in microorganisms in particular. YAKULT: THE PURSUIT OF In 1935 Yakult was PREVENTIVE MEDICINE established. Five years earlier, LEADS TO A FOCUS with the passionate desire to ON THE POWER OF “deliver good health to as many MICROORGANISMS people as possible”, Dr. Minoru Yakult was born out of the Shirota M.D., Ph.D. who was passion of Minoru Shirota, M.D., founder of Yakult succeeded in Ph.D (Fig.1). In the early 20th fortifying and culturing a strain century, when the future Dr. of beneficial Shirota was still a young man, that could reach the intestines poor hygiene and nutrition led alive, and set about providing to the deaths of many people in it in the form of a drink. Since Japan from infectious diseases then, the fruit of his passionate such as cholera and dysentery. desire has continued to spread Disturbed by this reality, the across the globe and, as of fiscal young man set his sights on 2019, Yakult’s products medicine and began studying are consumed daily by 40 at Kyoto Imperial University million people in 40 countries (now Kyoto University) in 1921. Figure 1. Dr Minoru Shirota (1899–1982). and regions. Yakult is imbued He started down the path of with this passionate desire from microorganism research, focusing alive, and produce beneficial SHIROTA-ISM: DR. our founding and it is part of on preventive medicine, which effects. This strain is now SHIROTA’S IDEAS REMAIN everything we do, including the places emphasis not on treating known as casei AT THE HEART OF ALL OUR development, manufacture and illnesses, but on trying to prevent strain Shirota. With the goal of BUSINESS ACTIVITIES sales of pharmaceuticals and them. As part of his research, providing this lactic acid bacteria Dr. Shirota proposed certain cosmetics. he discovered that lactic acid to as many people as possible, Dr. key ideas, such as preventive Under our corporate bacteria suppress harmful Shirota developed an affordable medicine, which together, we call philosophy of “we contribute bacteria in the intestines. In 1930, and delicious fermented Shirota-ism. This serves as the to the health and happiness he succeeded in strengthening drink and released it under the foundation and the guide for all of people around the world and culturing a strain of lactic name of Yakult in 1935. This of our business activities so that through pursuit of excellence acid bacteria that could survive marked the start of Yakult, which by “caring enough to make home in life science in general and digestive juices, such as gastric has since found popularity all deliveries”, we also strive for the our research and experience in fluid and bile, reach the intestines around the world. ideals of “sincerity” and “harmony

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among people”. microorganisms and using those The ideals of the company’s powers to further contribute founder have endured to the to health. present day, unchanged by time and today Shirota-ism is still at the RESEARCH AND heart of Yakult. DEVELOPMENT ACTIVITIES Since its founding, Yakult has AT YAKULT: ELUCIDATING consistently pursued research THE FUNCTION OF tapping into the potential of AND probiotics. With the goal of DEVELOPING PRODUCTS contributing to the healthy lives THAT CONTRIBUTE TO THE of as many people as possible, we HEALTH AND HAPPINESS will continue to devote our efforts OF PEOPLE to discovering new powers of Product development at Yakult, microorganisms and using those including for foods, cosmetics, powers to further contribute to and pharmaceuticals, is founded health. on research and development. In order to realize preventive YAKULT’S PROBIOTICS: medicine and contribute to MAKING USE OF OUR people’s health, we focus on CAREFULLY SELECTED, beneficial microorganisms, PROPRIETARY particularly the intestinal MICROORGANISMS microbiota, and investigate the Figure 2. Lactobacillus casei strain Shirota (stained green) incorporated in a macrophage The idea of using microorganisms relationship between the intestinal (the cytoplasm is stained red and the nucleus is stained blue). Findings suggested that the such as lactobacilli and microbiota and overall health macrophage is the key to the immune regulation of Lactobacillus casei strain Shirota. bifidobacteria as probiotics to from a variety of angles, including contribute to the health of people, molecular biology, immunology, RESEARCH AND potentially reducing the risk of has gathered an increasing physiology, and nutrition. We use ACHIEVEMENTS IN A cancer3. Some reductions in the amount of attention in recent the results of these efforts in the VARIETY OF AREAS: YAKULT risk of bladder4, colon5 and breast years. This concept is identical development of food, cosmetics, HAS MAINTAINED ITS FOCUS cancer6, among others, have to the “preventive medicine” and and pharmaceutical products. We ON PROBIOTICS WITH THE been reported. Lactobacillus casei “a healthy intestinal tract leads are also focused on investigating AIM OF ELUCIDATING THE strain Shirota is also known to be to a long life” ideas advocated microorganisms and natural BENEFITS OF LACTIC ACID effective in reducing the incidence by the company’s founder, Dr. products whose functions have BACTERIA AND INTESTINAL and mitigating the symptoms Shirota. Yakult has focused on the so far escaped notice and are BACTERIA of infectious diseases, such as potential of microorganisms since proactively researching these as Since its founding Yakult has infectious gastroenteritis caused its founding and through tireless potential new ingredients. been engaged in basic research by acute infantile diarrhea7, research continues to develop The Yakult Central Institute is of probiotics and intestinal upper respiratory tract infection8 products aimed at contributing the company’s hub for research microbiota, which are now and norovirus infection9. Recent to people’s health. Among these and development, and is the topics interesting many studies also showed that intake of probiotics are Lactobacillus casei comprised of seven buildings with researchers in the world. Yakult probiotics alleviated stress related strain Shirota. As a result of advanced research equipment and has collaborated with other symptoms10,11. a number of safety studies as facilities (Research Administration research institutions in recent well as long-term consumption Building, Basic Research years as part of its focus on LEADING THE WORLD studies as part of the company’s Building, Food Research Building, exploring the further potential of IN THE ELUCIDATION research activities, we have Pharmaceutical and Cosmetic probiotics. OF THE TRUE STATE OF been able to confirm that these Research Building, Quality and Years of research has shown INTESTINAL MICROBIOTA probiotics survive digestive juices Technical Development Building, that lactic acid bacteria bestow a AND INTESTINAL BACTERIA such as gastric fluid, reach the Common Use Facility Building, variety of benefits. The WITH ADVANCED RESEARCH intestines alive, and produce and Energy Supply Building). Lactobacillus casei strain Shirota is CAPABILITIES beneficial effects1. In this enriched environment, a case in point. Ingestion of this We have produced many results Since its founding, Yakult has we conduct a wide range of strain has been demonstrated in our research on intestinal consistently pursued research research including basic research, to regulate immunity in the microbiota. The Institute tapping into the potential of applied research focused on the body, including through the confirmed using the latest way probiotics. With the goal of development of food, cosmetic maintenance and restoration of that the bifidobacteria in the contributing to the healthy lives and pharmaceutical products, NK activity, which plays a vital mother transmit to the intestines of as many people as possible, we and an analysis business role in immunosurveillance2 of newborns12. The Institute also will continue to devote our efforts dedicated to safe production and (Fig.2). It also helps to rid the demonstrated that segmented to discovering new powers of environmental protection. body of harmful mutagens, filamentous bacteria (SFB), which

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Figure 3. Analysis of intestinal epithelial cells with a confocal laser scanning microscope. The induction of Th17 cells by segmented filamentous bacteria was visualized with immunofluorescence technique. are intestinal bacteria present in It is expected that improving 4. Aso Y, Akaza H, Kotake T, Tsukamoto Neurogastroenterol Motil. 2016;28:1027– T, Imai K, Naito S, the BLP Study Group 1036. same mammals, are involved in the intestinal environment will Preventive effect of a Lactobacillus 11. Takada M, Nishida K, Gondo Y, the induction of Th17 cells, a type have a positive effect on the casei preparation on the recurrence of Kikuchi-Hayakawa H, Ishikawa H, of T cell that plays an important reduction of antibiotics use superficial bladder cancer in a double- Suda K, Kawai M, Hoshi R, Kuwano blind trial. Eur Urol. 1995;27:104-109. Y, Miyazaki K, Rokutan K. Beneficial role in the defense system against and the response rate of the 5. Ishikawa H, Akedo I, Otani T, Suzuki effects of Lactobacillus casei strain Shirota the extracellular pathogens13 anticancer drug. T, Nakamura T, Takeyama I, Ishiguro on academic stress-induced sleep (Fig.3). Yakult also developed We remain actively engaged in S, Miyaoka E, Sobue T, Kakizoe T. disturbance in healthy adult: a double- Randomized trial of dietary fiber and blind, randomized, placebo-controlled YIF-SCAN®, a system that joint research with other cutting Lactobacillus casei administration for trial. Benef Microbes. 2017;8:153–162. enables highly efficient analysis of edge organizations, including prevention of colorectal tumors. Int J 12. Makino H, Kushiro A, Ishikawa E, intestinal microbiota14. Based on the Japan Aerospace Exploration Cancer. 2005;116:762-767. Muylaert D, Kubota H, Sakai T, Oishi K, 6. Toi M, Hirota S, Tomotaki A, Sato Martin R, Ben Amor K, Oozeer R, Knol genetic sequences unique to each Agency, a National Research N, Hozumi Y, Anan K, Nagashima T, J, Tanaka R. Transmission of intestinal species of intestinal microbiota, and Development Agency. We Tokuda Y, Masuda N, Ohsumi S, Ohno longum subsp. longum YIF-SCAN® selectively quantifies also launched joint research S, Takahashi M, Hayashi H, Yamamoto strains from mother to infant, determined by multilocus sequencing typing and the bacteria, enabling rapid, S, Ohashi Y. Probiotic beverage with soy operations with the Tohoku isoflavone consumption for breast cancer amplified fragment length polymorphism. precise analysis of a wide range of Medical Megabank Organization, prevention: A case-control study. Curr Appl Environ Microbiol. 2011;77:6788- bacteria, from abundant bacteria a National University Corporation, Nutr Food Sci. 2013;9:194-200. 6793. to those relatively few in number. in April 2018. This latter 7. Sur D, Manna B, Niyogi SK, 13. Atarashi K, Tanoue T, Ando M, Ramamurthy T, Palit A, Nomoto K, Kamada N, Nagano Y, Narushima S, Suda The results of research cooperation aims to help clarify Takahashi T, Shima T, Tsuji H, Kurakawa W, Imaoka, A, Setoyama H, Nagamori activities at Yakult are applied the physiological significance T, Takeda Y, Nair GB, Bhattacharya SK. T, Ishikawa E, Shima T, Hara T, Kado S, not only to product development, of the intake of fermented milk Role of probiotic in preventing acute Jinnohara T, Ohno, H, Kondo T, Toyooka diarrhoea in children: a community-based, K, Watanabe E, Yokoyama S, Tokoro S, but in a number of different fields drinks in terms of preventive randomized, double-blind placebo- Mori H, Noguchi Y, Morita H, Ivanov as well. One of our research medicine, and create new forms controlled field trial in an urban slum. II, Sugiyama T, Nuñez G, Camp JG, accomplishments that is now of preventive and therapeutic Epidemiol infect. 2011;139:919-926. Hattori M, Umesaki Y, Honda K. Th17 8. Fujita R, Iimuro S, Shinozaki T, Sakamaki Cell Induction by Adhesion of Microbes utilized in the medical field is medicine that target intestinal K, Uemura Y, Takeuchi A, Matsuyama to Intestinal Epithelial Cells. Cell. synbiotic therapy. Synbiotics microbiota. The cooperation is Y, Ohashi Y. Decreased duration of 2015;163:367-380. combines probiotics and expected to extend through the acute upper respiratory tract infections 14. Tsuji H, Matsuda K, Nomoto K. with daily intake of fermented milk: a Counting the Countless: Bacterial prebiotics, which function to end of 2020. multicenter, double-blinded, randomized Quantification by Targeting rRNA help increase the beneficial comparative study in users of day care Molecules to Explore the Human Gut bacteria in the intestines and References facilities for the elderly population. Am J Microbiota in Health and Disease. Front 1. Fujimoto J, Matsuki T, Sasamoto M, Infect Control. 2013;4:1231-1235. Microbiol. 2018;9:1417. strengthen gut barrier. Synbiotic Tomii Y, Watanabe K. Identification and 9. Nagata S, Asahara T, Ohta T, Yamada 15. Kanazawa H, Nagino M, Kamiya therapy is currently being used quantification of Lactobacillus casei strain T, Kondo S, Bian L, Wang C, Yamashiro Y, S, Komatsu S, Mayumi T, Takagi K, in medical institutions, where Shirota in human feces with strain- Nomoto K. Effect of the continuous intake Asahara T, Nomoto K, Tanaka R, Nimura specific primers derived from randomly of probiotic-fermented milk containing Y. Synbiotics reduce postoperative there have been numerous amplified polymorphic DNA. Int J Food Lactobacillus casei strain Shirota on infectious complications: a randomized reports of its usefulness in Microbiol. 2008;126:210-215. fever in a mass outbreak of norovirus controlled trial in biliary cancer patients preventing postoperative 2. Nagao F, Nakayama M, Muto T, gastroenteritis and the faecal microbiotia undergoing hepatectomy. 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